TERT expression attenuates metabolic disorders in obese mice by promoting adipose stem and progenitor cell expansion and differentiation
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Background and aims
Adipose tissue (AT) senescence, induced by obesity or aging, leads to a reduced capacity for tissue remodeling and a chronic pro-inflammatory state, which leads to the onset of metabolic pathologies. Cellular senescence is triggered by various stresses, in particular excessive shortening of telomeres, which activates the p21 pathway and leads to the arrest of the cell cycle. We used the mouse model p21+/Tert expressing TERT from the Cdkn1a locus to investigate whether counteracting telomere shortening by telomerase (TERT) specifically in pre-senescent cells could improve obesity-induced metabolic disorders.
Results
Our study demonstrates that conditional expression of TERT reduces insulin-resistance and glucose intolerance associated with obesity. In AT, this is accompanied by a decrease in the number of senescent p21-positive cells, very short telomeres, and oxidative DNA damage. Single nucleus RNA-seq data reveal TERT expression attenuates senescence induced by HFD in particular in adipose stem and progenitor cells (ASPC). We demonstrate that ASPC expansion and differentiation are promoted in p21+/Tert obese mice, thereby improving AT plasticity. Furthermore, we show that TERT expression enhances mitochondrial function and alleviates oxidative stress in ASPC. This process contributes to the AT hyperplasia with increased number of adipocytes which has been shown to have a protective effect against obesity-associated metabolic disorders.
Conclusions
These results underscore TERT's role in mitigating obesity-related metabolic dysfunction. Conditional TERT expression may therefore represent as a promising therapeutic strategy for obesity-associated metabolic disorders.
Adipose tissue (AT) senescence, induced by obesity or aging, leads to a reduced capacity for tissue remodeling and a chronic pro-inflammatory state, which leads to the onset of metabolic pathologies. Cellular senescence is triggered by various stresses, in particular excessive shortening of telomeres, which activates the p21 pathway and leads to the arrest of the cell cycle. We used the mouse model p21+/Tert expressing TERT from the Cdkn1a locus to investigate whether counteracting telomere shortening by telomerase (TERT) specifically in pre-senescent cells could improve obesity-induced metabolic disorders.
Results
Our study demonstrates that conditional expression of TERT reduces insulin-resistance and glucose intolerance associated with obesity. In AT, this is accompanied by a decrease in the number of senescent p21-positive cells, very short telomeres, and oxidative DNA damage. Single nucleus RNA-seq data reveal TERT expression attenuates senescence induced by HFD in particular in adipose stem and progenitor cells (ASPC). We demonstrate that ASPC expansion and differentiation are promoted in p21+/Tert obese mice, thereby improving AT plasticity. Furthermore, we show that TERT expression enhances mitochondrial function and alleviates oxidative stress in ASPC. This process contributes to the AT hyperplasia with increased number of adipocytes which has been shown to have a protective effect against obesity-associated metabolic disorders.
Conclusions
These results underscore TERT's role in mitigating obesity-related metabolic dysfunction. Conditional TERT expression may therefore represent as a promising therapeutic strategy for obesity-associated metabolic disorders.
Date Issued
2025-12-01
Date Acceptance
2025-09-25
Citation
Molecular Metabolism, 2025, 102
ISSN
2212-8778
Publisher
Elsevier
Journal / Book Title
Molecular Metabolism
Volume
102
Copyright Statement
© 2025 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
License URL
Publication Status
Published
Article Number
102262
Date Publish Online
2025-10-03